Fexaramine as an entry blocker for feline caliciviruses

Area of Science:

• Virology
• Antiviral Research
• Molecular Biology

Background:

• Feline calicivirus (FCV) causes significant oral and respiratory diseases in cats, with emerging virulent strains (vs-FCV) leading to high mortality.
• Current FCV vaccines have limited efficacy due to strain diversity and short-lasting immunity.
• There is an unmet need for effective antiviral therapies against FCV, particularly vs-FCV.

Purpose of the Study:

• To identify novel inhibitors of FCV, including virulent strains.
• To elucidate the mechanism of action of identified inhibitors.
• To investigate the potential for combination therapy and resistance development.

Main Methods:

• Cell culture experiments to screen for FCV inhibitors.
• Time-of-addition studies and resistant virus generation to determine mechanism of action.
• Reverse genetics system and mutational analysis to confirm resistance mutations.
• Comparative analysis with a protease inhibitor (NPI52).

Main Results:

• Fexaramine was identified as a potent inhibitor of FCV, including vs-FCV strains, acting as an entry blocker.
• A single amino acid change in the VP1 capsid protein conferred fexaramine resistance, confirmed via reverse genetics.
• Combination treatment with fexaramine and NPI52 was evaluated for its effect on FCV replication and resistance emergence.

Conclusions:

• Fexaramine represents a promising antiviral agent targeting FCV entry.
• Understanding resistance mechanisms is crucial for developing durable antiviral strategies.
• Combination therapies may offer enhanced efficacy and mitigate resistance development against FCV.